p-Cresol formation by cell-free extracts of Clostridium difficile

D'Ari, Linda; Barker, H. A.

doi:10.1007/bf00411256

Cited by 54 publications

(37 citation statements)

References 4 publications

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“…Sulfate depletion arises in the gut, both because of impaired transport of free sulfate in the bloodstream and impaired sulfate synthesis by eNOS [63,64]. Disruption of gut bacteria, exposure to toxic phenolic compounds necessary to enable sulfate transport, and deficient sulfate supply to the mucopolysaccharides in the gut all contribute to the leaky gut syndrome that is a common feature in autism [51].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, this unique phenotype is also associated with excess synthesis of p-cresol, via a pathway involved in tyrosine breakdown. These authors go on to propose that the known sulfate deficiency associated with autism [61,62] may be explained by the depletion of sulfate through sulfation of p-cresol produced from tyrosine by Clostridium difficile in the gut [63,64], in order to detoxify it. As we will explain in the next section, we believe that, in fact, p-cresol and other phenolic compounds are part of the solution rather than the cause, with respect to impaired sulfate transport.…”

Section: Gut Dysbiosis Autism and Colitismentioning

confidence: 99%

“…p-Cresol, formed via anaerobic metabolism of tyrosine by bacteria such as C. difficile [64], is a highly toxic carcinogen, which also causes adverse effects on the central nervous system, the cardiovascular system, lungs, kidney and liver [69]. A recent paper found that formula-fed infants had an overrepresentation of C. difficile in the gut bacteria [70].…”

Section: Gut Dysbiosis Autism and Colitismentioning

confidence: 99%

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Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases

Samsel

Seneff²

2013

Entropy

250

180

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Section: Discussionmentioning

confidence: 99%

Section: Gut Dysbiosis Autism and Colitismentioning

confidence: 99%

Section: Gut Dysbiosis Autism and Colitismentioning

confidence: 99%

See 1 more Smart Citation

Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases

Samsel

Seneff²

2013

Entropy

250

180

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“…It requires para hydroxyl substitution for oxidation of the aromatic alkyl group. Of those substrates tested, pCr elicits the greatest specific activity to PCMH, suggesting that pCr, a naturally occurring cresol (6,11,18) is the natural substrate for the enzyme. Results indicated that the PC-07 PCMH is not dependent on pyridine or flavin cofactors and therefore requires another, as yet unidentified, electron carrier protein. A likely candidate is azurin, a small copper-containing protein (1) determined to be the natural electron acceptor in aerobic Pseudomonas strains displaying PCMH activity (10,14).…”

Section: Discussionmentioning

confidence: 99%

Anaerobic oxidation of p-cresol mediated by a partially purified methylhydroxylase from a denitrifying bacterium

et al. 1989

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Anoxic cell extracts of a denitrifying bacterial isolate were shown to oxidize p-cresol to phydroxybenzoate. Oxidation of the substrate was independent of molecular oxygen and required nitrate as the natural terminal electron acceptor. Two enzyme activities were implicated in the pathway utilized by PC-07. A p-cresol methylhydroxylase mediated the oxidation ofp-cresol to p-hydroxybenzaldehyde, which was further oxidized to p-hydroxybenzoate by an NAD+-dependent dehydrogenase. The PC-07 methylhydroxylase was partially purified by anion-exchange chromatography. The protein appeared to be a multifunctional flavocytochrome, which first oxidized p-cresol to p-hydroxybenzyl alcohol, which was then oxidized to p-hydroxybenzaldehyde. The identity of the aldehyde was confirmed by mass spectroscopy. The PC-07 methylhydroxylase had a limited substrate range and required an alkyl-substituted phenolic ring with a hydroxyl group in the para position. From the available evidence, p-cresol, a naturally occurring phenol, exhibited the greatest affinity to the enzyme and therefore may be its natural substrate.A p-cresol (pCr)-utilizing, denitrifying bacterium, PC-07, has been previously isolated and described (4). The isolate is one member of a bacterial coculture comprising two denitrifying species which interdependently utilize pCr as the sole source of carbon for growth under anaerobic conditions (5). Initially, substrate oxidation to p-hydroxybenzoate (pOHB) is mediated by the PC-07 isolate and provides the ring fission substrate to the second member of the coculture; neither isolate is able to use the respective substrate of its partner for growth under anaerobic conditions. The PC-07 isolate, however, can utilize pCr as its sole source of carbon for growth under aerobic conditions. Studies with whole-cell suspensions of PC-07 have established the pathway for the anaerobic oxidation of pCr to pOHB via p-hydroxybenzyl alcohol and p-hydroxybenzaldehyde (pHBZ) intermediates. Substrate oxidation depends on the stoichiometric reduction of N03-to N2.The studies presented here further characterized the anaerobic oxidation of pCr by cell extracts of the PC-07 isolate. In addition, these studies described the partial purification and characterization of a pCr methylhydroxylase enzyme (PCMH) which mediates the initial oxidation of pCr. MATERIALS AND METHODS

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“…In the 1970's Clostridium difficile and Clostridium scatologenes were shown to produce p -cresol with p -hydroxyphenylacetate as the immediate precursor [Elsden et al, 1976]. Subsequently, pcresol formation by decarboxylation of p -hydroxyphenylacetate was reported for Lactobacillus strains [Yokoyama and Carlson, 1981] and for cell-free extracts of C. difficile [D'Ari and Barker, 1985].…”

Section: Occurrence and Biological Function Of The 4hpad Systemmentioning

confidence: 99%

Structure and Function of 4-Hydroxyphenylacetate Decarboxylase and Its Cognate Activating Enzyme

Selvaraj

Golding

Ullmann³

et al. 2016

Microb Physiol

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4-Hydroxyphenylacetate decarboxylase (4Hpad) is the prototype of a new class of Fe-S cluster-dependent glycyl radical enzymes (Fe-S GREs) acting on aromatic compounds. The two-enzyme component system comprises a decarboxylase responsible for substrate conversion and a dedicated activating enzyme (4Hpad-AE). The decarboxylase uses a glycyl/thiyl radical dyad to convert 4-hydroxyphenylacetate into p-cresol (4-methylphenol) by a biologically unprecedented Kolbe-type decarboxylation. In addition to the radical dyad prosthetic group, the decarboxylase unit contains two [4Fe-4S] clusters coordinated by an extra small subunit of unknown function. 4Hpad-AE reductively cleaves S-adenosylmethionine (SAM or AdoMet) at a site-differentiated [4Fe-4S]^2+/+ cluster (RS cluster) generating a transient 5′-deoxyadenosyl radical that produces a stable glycyl radical in the decarboxylase by the abstraction of a hydrogen atom. 4Hpad-AE binds up to two auxiliary [4Fe-4S] clusters coordinated by a ferredoxin-like insert that is C-terminal to the RS cluster-binding motif. The ferredoxin-like domain with its two auxiliary clusters is not vital for SAM-dependent glycyl radical formation in the decarboxylase, but facilitates a longer lifetime for the radical. This review describes the 4Hpad and cognate AE families and focuses on the recent advances and open questions concerning the structure, function and mechanism of this novel Fe-S-dependent class of GREs.

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p-Cresol formation by cell-free extracts of Clostridium difficile

Cited by 54 publications

References 4 publications

Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases

Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases

Anaerobic oxidation of p-cresol mediated by a partially purified methylhydroxylase from a denitrifying bacterium

Structure and Function of 4-Hydroxyphenylacetate Decarboxylase and Its Cognate Activating Enzyme

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